The immediate goal of this high-risk, high-payoff project is to develop a non-invasive assessment methodology of electrical activity in the retina of electronic retinal prosthesis recipients. The development and clinical evaluation of these retinal implants for patients blind from end-stage retinal degenerations has made considerable progress in the last several years and is being actively pursued by research groups and companies in at least a half dozen countries. Understanding the physiological response elicited by the electrical stimulus in the degenerated retina remains elusive, however, and there is an urgent need to uncover its mechanisms. It is known that the slow retinal degeneration process in human RP fundamentally alters the interactions between remaining retinal bipolar, amacrine, and ganglion cells;hence the use of animal models is of little help in understanding the activity in the retina of a blind implant recipient. Thus the development of noninvasive methods to assess this activity would be a major contribution towards understanding and improving the visual sensations reported by these patients. This proposal builds on multifocal clinical electrophysiology techniques, developed in the last two decades and widely used for diagnosis of retinal and visual pathway pathology, to investigate the retinal signals generated by uniform and patterned stimulation of implanted electrodes in retinal implant recipients. Pseudo-random on-off stimulation of the implanted electrodes, based on binary m-sequences, will elicit localized retinal responses and second-order interactions that will be extracted from a single corneal recording signal through well-established cross correlation techniques. Preliminary evidence suggests that the electrical stimulus artifact can be effectively reduced to reveal the retinal response activity, but a considerable effort is needed to perfect this approach to overcome the adverse signal to artifact ratio, adapt the stimulation and analysis techniques, optimize stimulation methods, estimate the strength of direct response signals and interactions, and develop ways to correlate physiological and psychophysical responses. A two-year project duration is proposed. PUBLIC HEALTH RELEVANCE: To elucidate the processes that take place during electrical stimulation of the retina in patients blind from retinal degenerations such as retinitis pigmentosa, a noninvasive stimulation and recording methodology will be developed. Such a technique is crucial for the interpretation of clinical findings with recently introduced retinal implants, and to advance the development of functional retinal prostheses.